Peptides and proteins are invaluable therapeutics and biological tools, where stimuli-responsive and fully reversible conjugation chemistry is essential to advances in drug delivery systems and chemical biology. However, methods that allow precise conjugation, efficient regulation of biochemical functions, and customized recovery of parent peptides remain underdeveloped. Here, we introduce a straightforward yet powerful reversible chemical strategy targeting methionine (Met), a widespread yet low abundance amino acid in peptides and proteins. By selectively alkylating Met-containing peptides under weakly acidic conditions, we form a stable C–S⁺ bond, which can be cleaved rapidly via 1,6-benzyl elimination upon stimulus. This versatile chemistry is demonstrated in diverse applications: (i) PEGylated prodrugs of antimicrobial peptides with reduced toxicity and enhanced enzymatic stability, (ii) esterase-responsive peptide–peptide inhibitor conjugates (PPICs) with improved cell membrane permeability and therapeutic effects, (iii) reversibly stapled peptides with switchable conformations for targeting both intra- and extracellular sites, and (iv) bioorthogonal control of C-terminal Met-caged neuropeptides. Overall, this work describes, for the first time, a valuable traceless modification strategy that promises to greatly benefit the peptide community and advance the field of chemical biology.

中文翻译：

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通过 1,6-苄基消除实现快速 C-S+ 键裂解，用于生物活性肽的无痕量修饰

肽和蛋白质是非常有价值的治疗方法和生物工具，其中刺激响应和完全可逆的偶联化学对于药物递送系统和化学生物学的进步至关重要。然而，允许精确偶联、有效调节生化功能和母肽定制回收的方法仍然不成熟。在这里，我们介绍了一种简单而强大的可逆化学策略，靶向蛋氨酸 （Met），甲硫氨酸 （Met） 是肽和蛋白质中一种广泛但丰度低的氨基酸。通过在弱酸性条件下选择性地烷基化含 Met 的肽，我们形成稳定的 C-S⁺ 键，该键可以在刺激时通过 1,6-苄基消除快速裂解。这种多功能化学方法已在各种应用中得到证明：（i） 毒性降低且酶稳定性增强的抗菌肽的聚乙二醇化前药，（ii） 酯酶反应性肽-肽抑制剂偶联物 （PPIC），具有改进的细胞膜通透性和治疗效果，（iii） 具有可切换构象的可逆装订肽，用于靶向细胞内和细胞外位点，以及 （iv） C 端 Met 笼神经肽的生物正交控制。总体而言，这项工作首次描述了一种有价值的无痕修饰策略，该策略有望极大地造福多肽界并推动化学生物学领域的发展。